Klinefelter syndrome

Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra

A person with typical untreated Klinefelter 46,XY/47,XXY mosaic, diagnosed at age 19 – a scar from biopsy is on his right breast above the nipple.

The Klinefelter syndrome has different manifestations and these will vary from one patient to another. Among the primary features are infertility and small, poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected. Whereas some other times symptoms are more prominent and may include weaker muscles, greater height, poor motor coordination, less body hair, gynecomastia (breast growth), and low libido. In the majority of the cases, these symptoms are noticed only at puberty.^[10][6][14]

Prenatal

An estimated 80% of pregnancies with fetuses having Klinefelter syndrome spontaneously abort. Generally, the severity of the malformations is proportional to the number of extra X chromosomes present in the karyotype. For example, patients with 49 chromosomes (XXXXY) have a lower IQ and more severe physical manifestations than those with 48 chromosomes (XXXY).^[15]

Physical manifestations

As babies and children, those with XXY chromosomes may have weaker muscles and reduced strength. They may sit up, crawl, and walk later than other infants. In average KS children will start walking at 19 months of age. They also have less muscle control and coordination than other children of their age.^[16]

During puberty, they show less muscular body, less facial and body hair, and broader hips. This is a direct consequence of the low levels of testosterone produced by KS subjects. Delays in motor development may occur, which can be addressed through occupational and physical therapies. As teens, males with XXY may develop breast tissue, have weaker bones, and a lower energy level than others. All of the testicles are affected and are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4ml in volume. Those with XXY chromosomes may also have microorchidism (i.e., small testicles).^[16][17]

By adulthood, they tend to become taller than average; with proportionally longer arms and legs, less-muscular bodies, more belly fat, wider hips, narrower shoulders. Some will show little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present in approximately a third of affected individuals, a slightly higher percentage than in the XY population. Approximately 10% of males with XXY chromosomes have gynecomastia noticeable enough that they may choose to have surgery. Those affected are often infertile, or have reduced fertility. Advanced reproductive assistance is sometimes possible in order to produce an offspring since approximately 50% of males with Klinefelter syndrome can produce sperm.^[11][18]

Psychological characteristics

Cognitive development

Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention. It is estimated that 10% of those with Klinefelter syndrome are autistic. Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing.^[19][20]

The overall IQ tends to be lower than average. Language milestones may also be delayed, particularly when compared to other people their age. Between 25% and 85% of males with XXY have some kind of language problem, such as delay in learning to speak, trouble using language to express thoughts and needs, problems reading, and trouble processing what they hear. They may also have a harder time doing work that involves reading and writing, but most hold jobs and have successful careers.^[16][21]

Behavior and personality traits

Compared to individuals with a normal number of chromosomes, males affected by Klinefelter syndrome may display behavioral abnormalities. These are phenotypically displayed as higher level of anxiety and depression, mood dysregulation, impaired social skills, emotional immaturity during childhood or difficulty with frustration.^[22][23][24] These neurocognitive abnormalities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome.^[25]

In 1995 a scientific study evaluated the psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. It demonstrated that males with XXY tend to be quiet, shy and undemanding; they are less self-confident, less active, and more helpful and obedient than other children their age. They may struggle in school and sports, meaning they may have more trouble "fitting in" with other kids.^[21][26]

As adults, they live lives similar to others without the condition; they have friends, families, and normal social relationships. Nonetheless, some individuals may experience social and emotional problems due to problems in childhood. They show a lower sex drive and low self esteem, in most cases due to the feminine characteristics that their bodies display.^[10][21]

Concomitant illness

Those with XXY are more likely than others to have certain health problems, such as

Klinefelter syndrome is not an inherited condition. The extra X chromosome comes from the mother in approximately 50% of the cases and the other 50% comes from the father. Maternal age is the only known risk factor. Women at 40 years have a four-times-higher risk of a child with Klinefelter syndrome than women aged 24 years.[13]^[31][32]

The extra chromosome is retained because of a

Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in approximately one in 500 live male births.[10]^[12][33]

In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as

Mosaicism

Approximately 15–20%^[38] of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges.^[38] Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only approximately 10 cases of 47,XXY/46,XX have been described in literature.^[39]

Random versus skewed X-inactivation

Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelter's, including in both cases a small proportion of individuals with a skewed ratio between the two Xs.^[40]

Pathogenesis

The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism.^[41] Despite this misunderstanding of the term, testicular growth is arrested.^[41]

Diagnosis

The standard diagnostic method is the analysis of the chromosomes' karyotype on

The symptoms of KS are often variable, so a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual.[10]

Prognosis

The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population.^[44] These results are still questioned data, are not absolute, and need further testing.^[45]

Treatment

As the genetic variation is irreversible, no causal therapy is available. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone-replacement therapy.^[46] Testosterone preparations are available in the form of syringes, patches, or gel. If gynecomastia is present, the surgical removal of the breast may be considered for both the psychological reasons and to reduce the risk of breast cancer.^[47][48]

The use of

dyspraxia.^[49]

Klinefelter syndrome has been identified in ancient burials. In August 2022, a team of scientists published a study of a skeleton found in Bragança, north-eastern Portugal, of a man who died around 1000 AD and was discovered by their investigations to have a 47,XXY karyotype.^[57] In 2021, bioarchaeological investigation of the individual buried with the Suontaka sword, previously assumed to be a woman, concluded he was a man with Klinefelter syndrome.^[58]

Epidemiology

This syndrome, evenly distributed in all

• Aneuploidy
• Intersex
• Turner syndrome
• XYY syndrome
• XXYY syndrome
• Taurodontism
• Trisomy X

References